Mechanisms underlying neonate specific metabolic effects of volatile anesthetics
- Seattle Children's Research Institute, United States
- University of Washington, United States
Abstract
Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
NIH Office of the Director (R01GM133865)
- Margaret M Sedensky
- Simon C Johnson
NIH Office of the Director (R01GM118514)
- Philip G Morgan
- Simon C Johnson
NIH Office of the Director (R00GM126147)
- Simon C Johnson
Northwest Mitochondrial Research Guild
- Simon C Johnson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Carlos Isales, Medical College of Georgia at Augusta University, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (Sedensky IACUC00070) at Seattle Children's Research Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments at Seattle Children's Research Institute. Every effort was made to minimize suffering.
Version history
- Received: December 3, 2020
- Preprint posted: December 9, 2020 (view preprint)
- Accepted: July 12, 2021
- Accepted Manuscript published: July 13, 2021 (version 1)
- Version of Record published: July 20, 2021 (version 2)
Copyright
© 2021, Stokes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mechanisms underlying neonate specific metabolic effects of volatile anesthetics
eLife 10:e65400.
https://doi.org/10.7554/eLife.65400
